About a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy, and others have suboptimal responses in at least one lineage. We have developed a program to ask whether use of a drug stimulating the c-mpl receptor, which binds the endogenous hormone thrombopoietin, could stimulate human hematopoietic stem cells in vivo. Murine, our own rhesus, and human data all suggest that thrombopoietin can stimulate primitive hematopoietic stem and progenitor cells to expand. The small molecule oral thrombopoietin mimetic eltrombopag was initially developed to overstimulate platelet production from marrow megakaryocytes to compensate for immune platelet destruction. We developed a protocol utilizing eltrombopag in a phase 1/2 clinical trial for patients with refractory severe aplastic anemia. We initially reported that eltrombopag had efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses (Olnes et al, NEJM 2012). We then reported additional safety and efficacy data on an expanded cohort of 43 patients, confirming an overall response rate or 40% with 3 to 4 months of treatment, including tri- and bilinear responses (Desmond et al, Blood, 2014). The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. During the current reporting period, we focused on an additional study, asking whether more prolonged administration of eltrombopag to patients with refractory SAA, for 6 months instead of 3 months, would improve response rate and rescue a larger fraction of refractory patients. This protocol is ongoing and has accrued 38 patients. To date, responses appear to be faster than on the initial trial, due to starting at full dose, in contrast to dose escalation in the original trial. The overall response rate appears similar, although there were patients that responded between 3 and 6 months, who would have been deemed non responders in the first trial. Samples were utilized to investigate pharmacokinetics of the drug in this patient population, demonstrating a very different kinetic pattern of drug availability compared to prior studies in ITP. In collaboration with Dr. Neal Young's and Dr. Andre Larochelle's research groups, we have investigated the impact of this treatment on genetic abnormalities in marrow failure, on in vivo and in vitro stem cell expansion and DNA damage repair, and identified a possible explanation for the effectiveness of eltrombopag in patients with SAA despite high endogenous TPO levels. This program resulted in FDA approval of a new labeled indication for eltrombopag in August 2014, and European commission approval in late 2015 for eltrombopag treatment of refractory aplastic anemia. This is the first new drug approved for aplastic anemia in decades and the first drug approved specifically for the refractory aplastic anemia patient population. These trials have now also expanded to treating a number of other bone marrow failure patient populations, as detailed in Dr. Neal Young's report.